Napoleonic Demons: Short telomeres trigger trouble for everyone

Abstract:
Like mischievous teenagers on a train, small numbers of telomeres can pull an emergency cord and stop the cell that carries them. These repeated stretches of DNA and associated proteins cap chromosome ends and play a key role in cellular life and death. When telomeres decay, chromosomes fuse with each other and spark genetic havoc that can lead to cancer (see "Intimate Liaisons") or induce a cell to commit suicide (see "More Than a Sum of Our Cells"). The consequences of telomere dysfunction are well established, but the exact trigger remains unknown. Several groups have studied the relation between cell survival and average telomere length. As a result, some investigators have concluded that telomeric length does not solely govern its function, because the cell can act up even when the average length remains generous. But new work shows that cells respond to individual chromosome ends rather than the average: Even a small number of shrunken telomeres can spur lethal events.

Hemann and colleagues generated mice with very short telomeres by inbreeding for six generations animals that lack telomerase, the enzyme that replenishes the short repeated sequences that compose telomeric DNA. Then they mated individuals from this strain with those with normal telomeres. The resulting offspring have long telomeres on half of their chromosomes and short ones on the other half. If average telomere length determines survival, the extent of cell suicide--or apoptosis--in these mice should fall halfway between that of the two parents. To probe this issue, the team analyzed cell death and found instead that the degree of apoptosis resembles that of the parent with short telomeres. This result suggests that the most diminutive telomeres--not the whole population--sabotage cells.

To find out whether the shriveled ends instigate global telomere trouble--inducing normal ends to inappropriately stick together, for example--the researchers assessed the relation between telomere length and misconduct. They used a fluorescent probe consisting of dye-labeled DNA that binds to the repeated sequences and emits a signal whose intensity is proportional to telomere length. Using this technique, they showed that chromosomes that most frequently fuse carry the shortest telomeres; chromosomes with long telomeres tend to behave properly.

Together, the results suggest that small numbers of miscreant telomeres set off the cellular alarms that lead to death. Apparently, although most telomeres are good passengers, a few deviants can slam on the brakes for the entire cell.